title: How conformational flexibility stabilizes the hyperthermophilic elongation factor G-domain.
abstract: Proteins from thermophilic organisms are stable and functional well above ambient temperature. Understanding the molecular mechanism underlying such a resistance is of crucial interest for many technological applications. For some time, thermal stability has been assumed to correlate with high mechanical rigidity of the protein matrix. In this work we address this common belief by carefully studying a pair of homologous G-domain proteins, with their melting temperatures differing by 40 K. To probe the thermal-stability content of the two proteins we use extensive simulations covering the microsecond time range and employ several different indicators to assess the salient features of the conformational landscape and the role of internal fluctuations at ambient condition. At the atomistic level, while the magnitude of fluctuations is comparable, the distribution of flexible and rigid stretches of amino-acids is more regular in the thermophilic protein causing a cage-like correlation of amplitudes along the sequence. This caging effect is suggested to favor stability at high T by confining the mechanical excitations. Moreover, it is found that the thermophilic protein, when folded, visits a higher number of conformational substates than the mesophilic homologue. The entropy associated with the occupation of the different substates and the thermal resilience of the protein intrinsic compressibility provide a qualitative insight on the thermal stability of the thermophilic protein as compared to its mesophilic homologue. Our findings potentially open the route to new strategies in the design of thermostable proteins.
authors.affiliation: Laboratoire de Biochimie Théorique, IBPC, CNRS, UPR9080, Université Paris Diderot , Sorbonne Paris Cité, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Kalimeri
authors.forename: Obaidur
authors.initials: O
authors.lastname: Rahaman
authors.forename: Simone
authors.initials: S
authors.lastname: Melchionna
authors.forename: Fabio
authors.initials: F
authors.lastname: Sterpone
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D004058:Diffusion; D004926:Escherichia coli / Q000378:metabolism; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D020653:Peptide Elongation Factor G / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D048229:Sulfolobus solfataricus / Q000378:metabolism; D044366:Transition Temperature
chemical_list: D001426:Bacterial Proteins; D020653:Peptide Elongation Factor G